Inverse 1,2,3-Triazole-1-yl-ethyl Substituted Hydroxamates as Highly Potent Matrix Metalloproteinase Inhibitors: (Radio)synthesis, in Vitro and First in Vivo Evaluation

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• 作者：Verena Hugenberg ; Burkhard Riemann ; Sven Hermann ; Otmar Schober ; Michael Sch盲fers ; Katrin Szardenings ; Artem Lebedev ; Umesh Gangadharmath ; Hartmuth Kolb ; Joseph Walsh ; Wei Zhang ; Klaus Kopka ; Stefan Wagner
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：September 12, 2013
• 年：2013
• 卷：56
• 期：17
• 页码：6858-6870
• 全文大小：597K
• 年卷期：v.56,no.17(September 12, 2013)
• ISSN：1520-4804

文摘

Noninvasive imaging and quantification of matrix metalloproteinase (MMP) activity in vivo are of great (pre)clinical interest. This can potentially be realized by using radiolabeled MMP inhibitors (MMPIs) as positron emission tomography (PET) imaging agents. Triazole-substituted MMPIs, discovered by our group, are highly potent inhibitors of MMP-2, -8, -9, and -13. The triazole ring and its position contribute significantly to the potency of the MMP inhibitor. To evaluate structure鈥揳ctivity relationships (SARs) of the initially discovered triazole-substituted MMPIs, an additional CH₂-group between the backbone of the molecule and the triazole core was inserted, and the triazole ring was 鈥渋nversed鈥?by switching the alkyne and azide groups. Similar to the original triazole-substituted hydroxamates, the inverse triazole MMPIs are excellent inhibitors with promising invivo properties. Pharmacokinetic properties and metabolic stability of an ¹⁸F-labeled candidate in mice were investigated.